GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Abstract

G-patch domain-containing proteins have emerged as pivotal regulators of RNA metabolism, and the dysfunction of these proteins has been linked to a large range of phenotypic traits. This study provides compelling evidence that biallelic mutations in GPATCH11 lead to severe early-onset photoreceptor degeneration, neurological issues, and skeletal abnormalities in humans. Analysis of exome datasets from affected individuals of four independent families identified variants in a new gene, GPATCH11. The aim of the study was to determine the genetic source of the patients symptoms and characterize the role of GPATCH11. Using engineered disease variants in mice, we showed abnormal levels of spliceosome components in mutant retinas and substantial splicing deregulation, indicating a role for GPATCH11 in spliceosome homeostasis and splicing activity. Additionally, we identified deregulated gene expression, partly independent of splicing abnormalities, suggesting the involvement of GPATCH11 in transcriptional regulation. The affected genes were found to be related to phototransduction and the transmission of visual messages, protein homeostasis, RNA homeostasis, and cilia metabolism. The presence of GPATCH11 in ciliary basal bodies further suggests a potential role in ciliary functions. Studying GPATCH11 dysfunction elucidates the complex roles of this protein in RNA metabolism, highlighting the significance of GPATCH11 in maintaining proper gene expression and its contributions to various aspects of retinal, neurological, and skeletal function or development. As demonstrated here, studying rare genetic disorders can help to define broader functions beyond the specific disease context, and study provides new insight into the broader roles of GPATCH11.